No Pain, Lots Of Gain

We’re all familiar with pain. Ranging from a stubbed toe to a severe injury, some level of pain is experienced on a near daily basis. But many of us are fortunate enough that our experiences with pain tend to be limited to relatively brief episodes that will eventually end, sooner or later. Yet for a growing percentage of the population, chronic pain is becoming more and more prevalent. This particular type of pain can be extremely difficult/near impossible to treat, and the necessary prescribed drugs can be dangerously addictive with serious side effects. In most instances strong drugs such as oxycodone and hydrocodone (Vicodin) tend to be used as treatment for chronic pain, and while effective they often cause gastrointestinal issues, drowsiness, and nausea. Fortunately, new insights into treating chronic pain may have the potential to alleviate these issues.

A particular wealth of information on chronic pain can be found in a small fraction of the population with a rare genetic condition. Born without the ability to feel pain, these individuals have a specific genetic mutation that causes their pain moderation system to be significantly altered. After coming to the attention of pain researcher John Wood at University College London, it was discovered that this condition and the resulting inability to feel pain is due to the lack of a particular voltage-gated sodium channel. Such channels are a major component in controlling communications between the brain and the rest of the nervous system by letting sodium ions travel in and out of cells. The sodium changes the voltage of the cellular membranes, which sets off chain reaction between cells and allows them to transmit information to and from the brain. In the instance that one of these channels is missing, certain signals might not reach the brain.

Thus with their role in brain communication, many of these channels are closely related to sensing and alleviating pain. When the nerves running through out bodies detect harmful stimuli (pain), a message is passed to the brain by activating the sodium channels. Once this message is received, the body reacts by releasing endogenous opioids (painkillers) to help mitigate the pain. These opioids are naturally produced peptides from which many synthetic painkillers are derived (i.e. oxycodone). They act by binding to receptors in the nervous system, and the amounts of opioids released are regulated by specific sodium channels. The opioids in turn dampen the pain signal traveling to the brain which helps to mitigate the level of pain that we feel. While amounts of endogenous opioids are usually not high enough to completely inhibit pain, our natural analgesic system can help us modulate pain to a certain point.

Researchers from Wood’s group kept this concept in mind as they postulated whether or not pharmaceutically blocking the sodium channel known to be missing in the pain-free population could induce similar effects in the clinic. Without the sodium channel present the body cannot regulate opioid peptides optimally, which allows for high levels of opioids to accumulate so that pain signals do not ever reach the brain. But surprisingly when the channel is blocked using an inhibitory drug, pain relief is minimal at best for clinical patients.

To probe this anomaly in sodium channel functionality, researchers gave mutant mice (lacking the sodium channel) a drug that prevents opioids from binding in the nervous system. Originally pain free, the mice were then able to feel a substantial amount of pain once their endogenous opioids were rendered ineffective. Consistent results were found when the experiment was repeated with a human patient. Wood realized that this is due to a minor amount of lingering sodium channel activity, as it is impossible to fully shut down all activity even at the most potent drug dosage. This is substantiated by the previous observation that complete analgesia can be accomplished with the combination of channel blockers and extremely low levels of exogenous opioids. Wood’s finding directly correlates the amount of opioids in the system to pain blocking capabilities, as even a minimal amount of channel activity prevents from large opioids from freely amassing.

By finding the link between low levels of sodium flux in the presence of the channel blocker and the inability to treat pain, Wood may have opened the door for new methods of treating chronic pain. His results promote the combined use of channel blockers and opioids for safer pain management, with a significantly lower risk of painkiller addiction.